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Renal ischemia/reperfusion (I/R) injury is a common clinical challenge faced by clinicians in kidney transplantation. I/R is the leading cause of acute kidney injury, and it occurs when blood flow to the kidney is interrupted and subsequently restored. I/R impairs renal function in both short and long terms. Renal ischemic preconditioning refers to all maneuvers intended to prevent or attenuate ischemic damage. In this context, the present review focuses on the dual-specificity phosphatase 3 (DUSP3), also known as vaccinia H1-related phosphatase, an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 has different biological functions: (1) it acts as a tumor modulator and (2) it is involved in the regulation of immune response, thrombosis, hemostasis, angiogenesis, and genomic stability. These functions occur either through MAPK-dependent or MAPK-independent mechanisms. DUSP3 genetic deletion dampens kidney damage and inflammation caused by I/R in mice, suggesting DUSP3 as a potential target for preventing renal I/R injury. Here, we discuss the putative role of DUSP3 in ischemic preconditioning and the potential mechanisms of such an attenuated inflammatory response via improved kidney perfusion and adequate innate immune response., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Large colon volvulus is a cause of colic in horses with high morbidity and mortality when not promptly treated. More treatment options are needed to improve the outcome of these cases by protecting against the damage caused by ischaemia and reperfusion injury., Objectives: To determine the effect of preconditioning with dexmedetomidine prior to induction of ischaemia-reperfusion (IR) injury in a large colon volvulus model in the horse., Study Design: Randomised blinded in vivo experiments., Methods: Horses received either a dexmedetomidine (DEX) or saline (CON) constant rate infusion (CRI) immediately following induction of anaesthesia. Venous, arterial, and transmural occlusion of a section of the large colon was performed for 3 h, after which the ligatures and clamps were removed to allow for reperfusion for 3 h. Biopsies of the large colon were taken at baseline, 1 and 3 h of ischaemia, and at 1 and 3 h of reperfusion., Results: The severity of crypt epithelial loss (DEX = 2.1 [0.8-2.8], CON = 3.1 [2.5-4], p = 0.03) and mucosal haemorrhage was decreased (DEX = 2.1 [1.3-3], CON = 3.5 [2.5-4], p = 0.03) in group DEX compared to group CON when graded on a scale of 0-4. Crypt length remained longer (DEX = 369.5 ± 91.7 μm, CON = 238.5 ± 72.6 μm, p = 0.02) and interstitium to crypt (I:C) ratio remained lower (DEX = 1.4 (1-1.7), CON = 2.6 [1.8-5.9], p = 0.03) in group DEX compared to group CON during reperfusion., Main Limitations: Clinical applicability of pharmacologic preconditioning is limited., Conclusion: Preconditioning with a dexmedetomidine CRI prior to IR injury demonstrated a protective effect histologically on the large colon in the horse. Further investigation into postconditioning with dexmedetomidine is warranted as a possible intervention in colic cases suspected of being large colon volvulus., (© 2024 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Background: Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC., Methods: First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects., Results: There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites., Conclusions: The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI., Competing Interests: J.S.R. reports funding from GSK and Sanofi and fees from Travere Therapeutics and Astex. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products associated with this research to declare., (Copyright: © 2024 Nordström et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To examine whether isoflurane preconditioning (IsoP) has a protective effect against renal ischemia/reperfusion injury (I/RI) in diabetic conditions and to further clarify the underlying mechanisms., Methods: Control and streptozotocin-induced diabetic rats were randomly assigned to five groups, as follows: normal sham, normal I/R, diabetic sham, diabetic I/R, and diabetic I/R + isoflurane. Renal I/RI was induced by clamping renal pedicle for 45 min followed by reperfusion for 24 h. IsoP was achieved by exposing the rats to 2% isoflurane for 30 min before vascular occlusion. Kidneys and blood were collected after reperfusion for further analysis. Renal histology, blood urea nitrogen, serum creatinine, oxidative stress, inflammatory cytokines, and renal cell apoptosis were assessed. Furthermore, the expression of brahma related gene 1 (Brg1), nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear factor-κB (NF-κB) were determined., Results: Compared with control, diabetic rats undergoing I/R presented more severe renal injury, oxidative stress, inflammatory reaction, and apoptosis with the impairment of Brg1/Nrf2/HO-1 signaling. All these alterations were significantly attenuated by pretreatment with isoflurane., Conclusions: These findings suggest that isoflurane could alleviate renal I/RI in diabetes, possibly through improving Brg1/Nrf2/HO-1 signaling.

This study investigated the antioxidant and neuroprotective effects of nicotinamide combined with ischemic preconditioning against cerebral ischemia reperfusion (CIR) injury. Thirty-five Wistar albino male rats were randomly divided into five groups: sham, preconditioned ischemia/reperfusion (IP+IR), ischemia/reperfusion (IR), preconditioned ischemia/reperfusion + nicotinamide (IP+IR+N), and ischemia/reperfusion + nicotinamide (IR+N). CIR was achieved with bilateral common carotid artery occlusion. IP+IR and IP+IR+N groups 30 min before ischemia; Three cycles of 10 sec ischemia/30 sec reperfusion followed by 20 min IR were applied. The IP+IR+N and IR+N groups received 500 mg/kg nicotinamide intraperitoneally. After 24 h of reperfusion, a neurological evaluation was performed and vertıcal pole test. Biochemically, malondialdehyde (MDA), glutathione (GSH) levels and catalase (CAT) activity were measured in blood and brain tissue samples. Rates of red neurons, sateliosis and spongiosis were determined histopathologically in the prefrontal cortex areas. After CIR, MDA levels increased significantly in serum and brain tissue in the IR group compared to the sham group, while GSH and CAT activity decreased in the brain tissue (p < 0.05). MDA levels in the tissues were found significantly decreased in the IR+N group compared to the IR group (p < 0.05). Administration of nicotinamide together with IP significantly decreased MDA levels in brain tissue and increased GSH and CAT activity (p < 0.05). Compared to the IR group, the morphological and neurological damage in the prefrontal cortex areas decreased in the IP+IR, IP+IR+N, and IR+N groups (p < 0.05). In addition, red neuron, sateliosis and spongiosis rates increased significantly in the IR group compared to the Sham, IP+IR+N, IR+N groups (p < 0.001 for all). In neurological evaluation, while the neurological score increased and the time on the vertical pole decreased significantly in the IR group, preconditioning, and nicotinamide groups reversed (p < 0.05). The study's results show that nicotinamide administration with ischemic preconditioning alleviates cerebral ischemia/reperfusion injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Ischemic stroke is a major cause of disability and mortality worldwide. Transcranial direct current stimulation (tDCS) and isoflurane (ISO) preconditioning exhibit neuroprotective properties. However, it remains unclear whether tDCS enhances the protective effect of ISO preconditioning on ischemic stroke, and the underlying mechanisms are yet to be clarified., Method: A model of middle cerebral artery occlusion (MCAO), a rat ischemia-reperfusion (I/R) injury model, and an in vitro oxygen-glucose deprivation/re-oxygenation (O/R) model of ischemic injury were developed. ISO preconditioning and tDCS were administered daily for 7 days before MCAO modeling. Triphenyltetrazolium chloride staining, modified neurological severity score, and hanging-wire test were conducted to assess infarct volume and neurological outcomes. Untargeted metabolomic experiments, adeno-associated virus, lentiviral vectors, and small interfering RNA techniques were used to explore the underlying mechanisms., Results: tDCS/DCS enhanced the protective effects of ISO pretreatment on I/R injury-induced brain damage. This was evidenced by reduced infarct volume and improved neurological outcomes in rats with MCAO, as well as decreased cortical neuronal death after O/R injury. Untargeted metabolomic experiments identified oxidative phosphorylation (OXPHOS) as a critical pathological process for ISO-mediated neuroprotection from I/R injury. The combination of tDCS/DCS with ISO preconditioning significantly inhibited I/R injury-induced OXPHOS. Mechanistically, Akirin2, a small nuclear protein that regulates cell proliferation and differentiation, was found to decrease in the cortex of rats with MCAO and in cortical primary neurons subjected to O/R injury. Akirin2 functions upstream of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). tDCS/DCS was able to further upregulate Akirin2 levels and activate the Akirin2/PTEN signaling pathway in vivo and in vitro, compared with ISO pretreatment alone, thereby contributing to the improvement of cerebral I/R injury., Conclusion: tDCS treatment enhances the neuroprotective effects of ISO preconditioning on ischemic stroke by inhibiting oxidative stress and activating Akirin2-PTEN signaling pathway, highlighting potential of combination therapy in ischemic stroke., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Perioperative acute kidney injury (AKI), which is mainly mediated by renal ischemia‒reperfusion (I/R) injury, is commonly observed in clinical practice. However, effective measures for preventing and treating this perioperative complication are still lacking in the clinic. Thus, we designed this study to examine whether remote liver ischemic preconditioning (RLIPC) has a protective effect on damage caused by renal I/R injury. In a rodent model, 30 mice were divided into five groups to assess the effects of RLIPC and ERK1/2 inhibition on AKI. The groups included the sham-operated (sham), kidney ischemia and reperfusion (CON), remote liver ischemic preconditioning (RLIPC), CON with the ERK1/2 inhibitor U0126 (CON+U0126), and RLIPC with U0126 (RLIPC+U0126). RLIPC consisted of 4 liver ischemia cycles before renal ischemia. Renal function and injury were assessed through biochemical assays, histology, cell apoptosis and protein phosphorylation analysis. RLIPC significantly mitigated renal dysfunction, tissue damage, inflammation, and apoptosis caused by I/R, which was associated with ERK1/2 phosphorylation. Furthermore, ERK1/2 inhibition with U0126 negated the protective effects of RLIPC and exacerbated renal injury. To summarize, we demonstrated that RLIPC has a strong renoprotective effect on kidneys post I/R injury and that this effect may be mediated by phosphorylation of ERK1/2., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Cerebral ischemia reperfusion injury (CIRI) often leads to deleterious complications after stroke patients receive reperfusion therapy. Exercise preconditioning (EP) has been reported to facilitate brain function recovery. We aim to explore the specific mechanism of EP in CIRI., Methods: Sprague-Dawley rats were randomized into Sham, middle cerebral artery occlusion (MCAO), and EP groups (n = 11). The rats in the EP group received adaptive training for 3 days (10 m/min, 20 min/day, with a 0° incline) and formal training for 3 weeks (6 days/week, 25 m/min, 30 min/day, with a 0° incline). Then, rats underwent MCAO surgery to establish CIRI models. After 48 h, neurological deficits and cerebral infarction of the rats were measured. Neuronal death and apoptosis in the cerebral cortices were detected. Furthermore, RNA sequencing was conducted to investigate the specific mechanism of EP on CIRI, and qPCR and Western blotting were further applied to confirm RNA sequencing results., Results: EP improved neurological deficit scores and reduced cerebral infarction in MCAO rats. Additionally, pre-ischemic exercise also alleviated neuronal death and apoptosis of the cerebral cortices in MCAO rats. Importantly, 17 differentially expressed genes (DEGs) were identified through RNA sequencing, and these DEGs were mainly enriched in the HIF-1 pathway, cellular senescence, proteoglycans in cancer, and so on. qPCR and Western blotting further confirmed that EP could suppress TIMP1, SOCS3, ANGPTL4, CDO1, and SERPINE1 expressions in MCAO rats., Conclusion: EP can improve CIRI in vivo, the mechanism may relate to TIMP1 expression and HIF-1 pathway, which provided novel targets for CIRI treatment., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Necrotising enterocolitis (NEC) has a complex pathophysiology but the common end-point is ischaemia reperfusion injury (IRI) and intestinal necrosis. We have previously reported that RIC significantly reduces the intestinal injury in a rat model of NEC. Here we describe the changes in intestinal mRNA occurring in the intestine of animals exposed to IRI, both with and without RIC. Related rat-pups were randomly assigned to four groups: SHAM, IRI only, RIC only and RIC + IRI. IRI animals, underwent 40 min of intestinal ischaemia, and 90 min of reperfusion. Animals that underwent RIC had three cycles of 5 min of alternating ischaemia/reperfusion by means of a ligature applied to the hind limb. Samples from the terminal ileum were immediately stored in RNA-preserving media for later next generation sequencing and transciptome analysis using R v 3.6.1. Differential expression testing showed that 868 genes differentially expressed in animals exposed to RIC alone compared to SHAM and 135 in the IRI and RIC group compared to IRI alone. Comparison between these two sets showed that 25 genes were differentially expressed in both groups. Pro-inflammatory molecules: NF-ĸβ2, Cxcl1, SOD2 and Map3k8 all show reduced expression in response to RIC. Targeted gene analysis revealed increased expression in PI3K which is part of the so-called RISK-pathway which is a key part of the protective mechanisms of RIC in the heart. Overall, this transcriptomic analysis shows that RIC provides a protective effect to the intestine via anti-inflammatory pathways. This could be particularly relevant to treating and preventing NEC., (© 2024. The Author(s).)

Acute kidney injury (AKI) is common following liver transplantation and is associated with liver ischeamia reperfusion (IR) injury. The purpose of this study was to use a mouse model of liver IR injury and AKI to study the role of Neutrophil Gelatinase Associated Lipocalin (NGAL), a biomarker of AKI, in liver IR injury and AKI. We demonstrate an adapted, reproducible model of liver IR injury and AKI in which remote ischemic preconditioning (RIPC) by repeated episodes of hindleg ischemia prior to liver IR reduced the severity of the IR injury. In this model, serum NGAL at 2 h post reperfusion correlated with AKI development early following IR injury. This early rise in serum NGAL was associated with hepatic but not renal upregulation of NGAL mRNA, suggesting NGAL production in the liver but not the kidney in the early phase post liver IR injury.

Background/aim: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC)., Materials and Methods: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury., Results: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model., Conclusion: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Remote ischemic preconditioning reduces ischemia-reperfusion injury in patients undergoing hepatectomy. Moreover, there is evidence that the protective effects of remote ischemic preconditioning may be more pronounced in pre-damaged livers. The objective of this trial was to investigate the extent to which remote ischemic preconditioning can attenuate ischemia-reperfusion injury after hepatectomy and Pringle maneuver in patients with chronic liver disease., Methods: In this randomized, controlled, triple-blind monocenter trial, a total of 102 patients with chronic liver disease and planned hepatectomy were enrolled between December 2019 and March 2022. Eligible patients were randomized to the remote ischemic preconditioning or sham arms. Remote ischemic preconditioning was induced through 3 10-minute cycles of alternating ischemia and reperfusion of the upper extremity. The study was prospectively registered in the German Clinical Trials Registry (DRKS00018931)., Results: A total of 102 patients were included in the study and were randomized (51 per arm). The median age was 69.5 years, approximately two-thirds of the patients were male (69/102, 67.7%), and the mean body mass index was 25.6 kg/m 2 . Most patients were classified as American Society of Anesthesiologists II (55/102, 53.9%) or III (45/102, 44.1%). The primary endpoint, the transaminases on the first postoperative day (alanine aminotransferase /aspartate aminotransferase: remote ischemic preconditioning arm: 250 (35-1721)/320 (42-1525) U/L versus sham control arm: 283 (32-792)/356 (20-1851) U/L, P = .820/0.639), clinical outcomes as well as remote ischemic preconditioning biomarker levels were comparable between both arms., Conclusion: Remote ischemic preconditioning did not achieve a significant reduction in postoperative transaminase levels, nor did it affect clinical results and biomarkers., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Remote ischemic preconditioning (RIPC) protects organs from ischemia-reperfusion injury. Recent trials showed that RIPC improved gas exchange in patients undergoing lung or cardiac surgery. We performed a systematic search to identify randomized controlled trials involving RIPC in surgery under general anesthesia. The primary outcome was the P a O 2 /F I O 2 (P/F) ratio at 24 h after surgery. Secondary outcomes were A-a DO 2 , the respiratory index, duration of postoperative mechanical ventilation (MV), incidence of acute respiratory distress syndrome (ARDS), and serum cytokine levels. The analyses included 71 trials comprising 7854 patients. Patients with RIPC showed higher P/F ratio than controls (mean difference [MD] 36.6, 95% confidence interval (CI) 12.8 to 60.4, I 2  = 69%). The cause of heterogeneity was not identified by the subgroup analysis. Similarly, A-a DO 2 (MD 15.2, 95% CI - 29.7 to - 0.6, I 2  = 87%) and respiratory index (MD - 0.17, 95% CI - 0.34 to - 0.01, I 2  = 94%) were lower in the RIPC group. Additionally, the RIPC group was weaned from MV earlier (MD - 0.9 h, 95% CI - 1.4 to - 0.4, I 2  = 78%). Furthermore, the incidence of ARDS was lower in the RIPC group (relative risk 0.73, 95% CI 0.60 to 0.89, I 2  = 0%). Serum TNFα was lower in the RIPC group (SMD - 0.6, 95%CI - 1.0 to - 0.3 I 2  = 87%). No significant difference was observed in interleukin-6, 8 and 10. Our meta-analysis suggested that RIPC improved oxygenation after surgery under general anesthesia.Clinical trial number: This study protocol was registered in the University Hospital Medical Information Network (registration number: UMIN000030918), https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000035305., (© 2023. Springer Nature Limited.)

Hepatic ischemia-reperfusion injury (HIRI) usually occurs during subtotal hepatectomy and severely damages liver function during the perioperative period. Endoplasmic reticulum stress (ERS) dependent apoptosis has been suggested to play a crucial role in HIRI progression. The present study focused on the regulatory effect of autophagy activation induced by ischemic preconditioning (IPC) on ERS-dependent apoptosis of hepatocytes in HIRI. A HIRI mouse model and oxygen-glucose deprivation/reperfusion (OGD/R) AML-12 hepatocyte cell lines were constructed to evaluate the protective effect of IPC in vivo and in vitro. The protein levels of p-eIF2α, CHOP, and cleaved caspase-12 were used to evaluate the ERS-dependent apoptosis, whereas LC3-II and p62 were considered as the autophagy activation markers. The beneficial molecular chaperones GRP78, HSP60, and HSP70 were also tested to evaluate autophagy. HIRI significantly increased ERS-dependent apoptosis markers and the number of apoptotic cells and damaged liver function. The ERS inhibitor salubrinal significantly alleviated liver injury in HIRI and OGD/R hepatocytes. Furthermore, both remote IPC and direct IPC significantly alleviated liver injury and inflammatory cell infiltration. IPC also upregulated LC3-II, downregulated p62 expression, and increased the mRNA levels of GRP78, HSP60, and HSP70 in HIRI mice and OGD/R hepatocytes, indicating the activation of autophagy by IPC. The autophagy inhibitor 3-methyladenine significantly attenuated the protective effects of IPC on ERS-dependent apoptosis and liver function, whereas the autophagy activator rapamycin mimicked the protective effects of IPC on ERS-dependent apoptosis in vivo and in vitro, suggesting a regulatory role of autophagy in ERS-dependent apoptosis. These results demonstrated that IPC could induce moderate autophagy and upregulate a few molecular chaperones to strengthen endogenous defense mechanisms, which is beneficial for alleviating ERS-dependent apoptosis and protecting hepatocytes from HIRI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Free muscular flaps are commonly used in plastic surgery. The main reason of failure is thrombosis induced by a phenomenon called ischemia reperfusion. Preconditioning showed an interest to prevent ischemia reperfusion injury in transplantation surgery. The aim of the study is to evaluate the effect of ischemic preconditioning on skeletal tissue tolerance after warm venous ischemia., Materials and Methods: We realized an experimental study with latissimus dorsi flaps of 12 pigs, divided in 6 groups in function of their time of preconditioning and duration of warm venous ischemia. A morphologic analysis was performed measuring cell's diameter and interstitial tissue area and notifying the presence or absence of neutrophils, necrosis or intravascular thrombosis. To detect inflammation, necrosis or hypoxia, immunohistochemistry was effectuated using the follow primary antibodies, AIF, HIF1 alpha, caspase 3, SOD 1 and PKC epsilon. TUNEL assay showed apoptosis cells, were realized. One way Anova test was performed to compare the quantitative evolution over time of histological parameters and rate of apoptosis., Results: Preconditioning of 40min or 1hour allowed to reduced ischemia reperfusion lesions: no cellular or interstitial oedema, reduction of neutrophils infiltrate and intravascular thrombus. TUNEL assay showed a higher rate of apoptosis nucleus for the control group E compared to preconditioning group C and D. Immunohistochemistry results were no relevant., Conclusion: We showed a diminution of lesions of ischemia reperfusion for experimental groups with preconditioning: diminution of interstitial oedema, of cellular oedema, diminution of neutrophils infiltrated and level of apoptosis cells. Preconditioning of 40minutes were as efficient as one hour., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: Remote ischaemic conditioning (RIC) has been shown to reduce ischaemia-reperfusion injury(IRI) in multiple organ systems. IRI is seen in multiple bowel pathologies in the newborn, including NEC. We investigated the potential of RIC as a novel therapy for various intestinal pathologies in the newborn., Methods: We used an established intestinal IRI model in rat pups which results in similar intestinal injury to necrotising enterocolitis (NEC). Animals were randomly allocated to IRI only(n = 14), IRI + RIC(n = 13) or sham laparotomy(n = 10). The macroscopic extent of intestinal injury is reported as a percentage of total small bowel. Injury severity was measured using Chiu-Park scoring. Neutrophil infiltration/activation was assayed by myeloperoxidase activity. Immunohistochemistry was used to assess the expression of hypoxia-inducible factor alpha (HIF-1α). Data are median (interquartile range)., Results: Animals that underwent RIC showed a decreased extent of macroscopic injury from 100%(85-100%) in the IRI only group to 58%(15-84%, p = 0.003) in the IRI + RIC group. Microscopic injury score was significantly lower in animals that underwent RIC compared to IRI alone (3.5[1.25-5] vs 5.5[4-6], p = 0.014). Intestinal myeloperoxidase activity in animals exposed to IRI was 3.4 mU/mg of tissue (2.5-3.7) and 2.1 mU/mg(1.5-2.8) in the IRI + RIC group(p = 0.047). HIF-1α expression showed a non-significant trend towards reduced expression in the IRI + RIC group., Conclusions: RIC reduces the extent and severity of bowel injury in this animal model, supporting the hypothesis that RIC has therapeutic potential for intestinal diseases in the newborn., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a global health problem and has recently been recognized as a risk factor for developing chronic kidney disease (CKD). Unfortunately, there are no effective treatments to reduce or prevent AKI, which results in high morbidity and mortality rates. Ischemic preconditioning (IPC) has emerged as a promising strategy to prevent, to the extent possible, renal tissue from AKI. Several studies have used this strategy, which involves short or long cycles of ischemia/reperfusion (IR) prior to a potential fatal ischemic injury. In most of these studies, IPC was effective at reducing renal damage. Since the first study that showed renoprotection due to IPC, several studies have focused on finding the best strategy to activate correctly and efficiently reparative mechanisms, generating different modalities with promising results. In addition, the studies performing remote IPC, by inducing an ischemic process in distant tissues before a renal IR, are also addressed. Here, we review in detail existing studies on IPC strategies for AKI pathophysiology and the proposed triggering mechanisms that have a positive impact on renal function and structure in animal models of AKI and in humans, as well as the prospects and challenges for its clinical application.

Consumption of high-fat diet (HFD) promotes mitochondrial dysfunction and the latter act as a critical factor in determining the severity of ischemia-reperfusion (IR) injury in different cell types. Ischemic preconditioning (IPC), a well-known protocol that render IR protection in kidney works via mitochondria. In the present study, we evaluated how HFD kidney with underlying mitochondrial changes respond to precondition protocol after IR induction. Wistar male rats were used in this study and were divided into two groups: SD (standard diet; n = 18) and HFD (high-fat diet; n = 18), which were further subdivided into sham, ischemia-reperfusion, and precondition groups at the end of the dietary regimen. Blood biochemistry, renal injury marker, creatinine clearance (CrCl), mitochondrial quality (fission, fusion, and phagy), mitochondrial function via ETC enzyme activities and respiration, and signalling pathway were analysed. Sixteen weeks of HFD administration to the rat deteriorated the renal mitochondrial health measured via 10% decline in mitochondrial respiration index ADP/O (in GM), reduced mitochondrial copy number (55%), biogenesis (56%), low bioenergetics potential (19% complex I + III and 15% complex II + III), increased oxidative stress, and reduced expression of mitochondrial fusion genes compared with SD rats. IR procedure in HFD rat kidney inflicted significant mitochondrial dysfunction and further deteriorated copy number along with impaired mitophagy and mitochondrial dynamics. IPC could effectively ameliorate the renal ischemia injury in normal rat but failed to provide similar kind of protection in HFD rat kidney. Even though the IR-associated mitochondrial dysfunction in both normal and HFD rats were similar, the magnitude of overall dysfunction and corresponding renal injury and compromised physiology was high in HFD rats. This observation was further confirmed via in vitro protein translation assay in isolated mitochondria from normal and HFD rat kidney that showed significantly reduction in the response ability of mitochondria in HFD. In conclusion, the deteriorated mitochondrial function and its quality along with low mitochondrial copy number and downregulation of mitochondrial dynamic gene exhibited by HFD rat kidney augments the sensitivity of renal tissue towards the IR injury which leads to the compromised protective ability by ischemic preconditioning., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Remote ischemic preconditioning (RIPC) refers to a brief episode of exposure to potential adverse stimulation and prevents injury during subsequent exposure. RIPC has been shown to increase tolerance to ischemic injury and improve cerebral perfusion status. Exosomes have a variety of activities, such as remodeling the extracellular matrix and transmitting signals to other cells. This study aimed to investigate the potential molecular mechanism of RIPC-mediated neuroprotection., Methods: Sixty adult male military personnel participants were divided into the control group (n = 30) and the RIPC group (n = 30). We analyzed the differential metabolites and proteins in the serum exosomes of RIPC participants and control subjects., Results: Eighty-seven differentially expressed serum exosomal metabolites were found between the RIPC and control groups, which were enriched in pathways related to tyrosine metabolism, sphingolipid metabolism, serotonergic synapses, and multiple neurodegeneration diseases. In addition, there were 75 differentially expressed exosomal proteins between RIPC participants and controls, which involved the regulation of insulin-like growth factor (IGF) transport, neutrophil degranulation, vesicle-mediated transport, etc. Furthermore, we found differentially expressed theobromine, cyclo gly-pro, hemopexin (HPX), and apolipoprotein A1 (ApoA1), which are associated with neuroprotective benefits in ischemia/reperfusion injury. In addition, five potential metabolite biomarkers, including ethyl salicylate, ethionamide, piperic acid, 2, 6-di-tert-butyl-4-hydroxymethylphenol and zerumbone, that separated RIPC from control individuals were identified., Conclusion: Our data suggest that serum exosomal metabolites are promising biomarkers for RIPC, and our results provide a rich dataset and framework for future analyses of cerebral ischemia‒reperfusion injury under ischemia/reperfusion conditions., (© 2023. The Author(s).)

Background: To investigate the protective effects of exosomes extracted from splenic ischemic preconditioning (sIPC) models on renal ischemia-reperfusion injury (IRI)., Methods: sIPC was conducted on mice before renal IRI, and exosomes derived from sIPC mice were infused into a mouse model of renal IRI. The kidney tissue and serum were collected 24 h later. The morphological changes, inflammation and apoptosis in IR kidneys were determined by hematoxylin-eosin (HE), terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and Ki-67 immunohistochemical staining. In addition, the proinflammatory cytokines in serum and cell supernatant were measured with enzyme-linked immunosorbent assays (ELISAs). Then, we administered exosomes to mouse renal epithelial cells. TUNEL assays and flow cytometry were used to evaluate cell apoptosis. Bax and Bcl-2 levels were measured via Western blotting., Results: HE staining showed that the renal IRI was attenuated after sIPC. TUNEL results showed that renal tissue apoptosis was greatly reduced after sIPC or injection of exosomes. ELISAs showed that the serum creatinine (sCr), tumor necrosis factor alpha, and interleukin-1 β levels induced by IRI decreased with sIPC. In vitro, exosomes extracted from the hypoxia/reoxygenation (H/R) splenic fibroblast model had the same protective effect. TUNEL and flow cytometry results showed that the exosomes reduced apoptosis. ELISAs showed that tumor necrosis factor alpha and interleukin-1 β were significantly increased in the H/R group but decreased due to the exosomes treated with starvation. WB results showed that Bax expression was increased and Bcl-2 expression was decreased in the H/R group. However, exosomes decreased the Bax level and increased the Bcl-2 level., Conclusions: Exosomes extracted from sIPC models exerted a protective effect to attenuate renal IRI., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Individual tissues have significantly different resistance to ischemia-reperfusion damage. There is still no adequate treatment for the consequences of ischemia-reperfusion damage. By utilizing ischemic tolerance, it is possible to achieve a significant reduction in the extent of the cell damage due to ischemia-reperfusion injury. Since ischemia-reperfusion damage usually occurs unexpectedly, the use of preconditioning is extremely limited. In contrast, postconditioning has wider possibilities for use in practice. In both cases, the activation of ischemic tolerance can also be achieved by the application of sublethal stress on a remote organ. Despite very encouraging and successful results in animal experiments, the clinical results have been disappointing so far. To avoid the factors that prevent the activation of ischemic tolerance, the solution has been to use blood plasma containing tolerance effectors. This plasma is taken from healthy donors in which, after exposure to two sublethal stresses within 48 h, effectors of ischemic tolerance occur in the plasma. Application of this activated plasma to recipient animals after the end of lethal ischemia prevents cell death and significantly reduces the consequences of ischemia-reperfusion damage. Until there is a clear chemical identification of the end products of ischemic tolerance, the simplest way of enhancing ischemic tolerance will be the preparation of activated plasma from young healthy donors with the possibility of its immediate use in recipients during the initial treatment.

Remote ischemic preconditioning (RIPC) has been shown to minimize subsequent ischemia-reperfusion injury (IRI), whereas obesity has been suggested to attenuate the efficacy of RIPC in animal models. The primary objective of this study was to investigate the effect of a single bout of RIPC on the vascular and autonomic response after IRI in young obese men. A total of 16 healthy young men (8 obese and 8 normal weight) underwent two experimental trials: RIPC (three cycles of 5 min ischemia at 180 mmHg + 5 min reperfusion on the left thigh) and SHAM (the same RIPC cycles at resting diastolic pressure) following IRI (20 min ischemia at 180 mmHg + 20 min reperfusion on the right thigh). Heart rate variability (HRV), blood pressure (SBP/DBP), and cutaneous blood flow (CBF) were measured between baseline, post-RIPC/SHAM, and post-IRI. The results showed that RIPC significantly improved the LF/HF ratio ( p = 0.027), SBP ( p = 0.047), MAP ( p = 0.049), CBF ( p = 0.001), cutaneous vascular conductance ( p = 0.003), vascular resistance ( p = 0.001), and sympathetic reactivity (SBP: p = 0.039; MAP: p = 0.084) after IRI. However, obesity neither exaggerated the degree of IRI nor attenuated the conditioning effects on the measured outcomes. In conclusion, a single bout of RIPC is an effective means of suppressing subsequent IRI and obesity, at least in Asian young adult men, does not significantly attenuate the efficacy of RIPC.

Objective: Ischemia reperfusion injury greatly damages liver function and deteriorates the prognosis of patients undergoing partial hepatectomy. This study is to compare the protective efficiency of direct and remote ischemic preconditioning (DIPC and RIPC) on ischemia reperfusion injury of the liver in patients undergoing partial hepatectomy., Methods: 90 patients scheduled for partial hepatectomy were enrolled and randomly divided into control ( n = 30), DIPC ( n = 30), and RIPC ( n = 30) groups. Baseline and surgery characteristics were collected, and ischemic preconditioning methods were carried out. Intraoperative hemodynamics, liver function and liver reserve capacity, oxidative stress, and inflammatory responses were measured, and the incidence of postoperative adverse reactions was calculated finally., Results: 10 patients were excluded from the study, and finally, the eligible patients in three groups were 27, 28, and 25, separately. No significant differences were observed in baseline and surgery characteristics among the three groups. SBP and DBP were significantly higher after hepatic portal vein occlusion while they were significantly lower after surgery in the DIPC and RIPC groups compared with that in the control group, SBP and DBP were of great fluctuation at different time points in the control group while they showed much more stabilization in the DIPC and RIPC groups. ALT, AST, and TBIL were significantly decreased on days 1, 3, and 5 after surgery, and ICG R15 was significantly decreased while ICG K value and EHBF were significantly increased on day 1 after surgery in the DIPC and RIPC groups compared with that in the control group. Moreover, antioxidant enzyme SOD was increased, and inflammatory factors TNF- α and IL-1 β were decreased 24 hours after surgery in the DIPC and RIPC groups compared with that in the control group. DIPC and RIPC also decreased hospital stays and the incidence of nausea, vomiting, and hypertension., Conclusion: DIPC and RIPC both alleviated ischemia reperfusion injury of the liver and reduced perioperative complications with similar protective efficiency in patients undergoing partial hepatectomy., Competing Interests: The authors declare that there were no competing interests., (Copyright © 2023 Erliang Kong et al.)

PURPOSE OF THE STUDY The purpose of this study was to minimize tourniquet-induced ischemia-reperfusion injury (IRI) in total knee arthroplasty (TKA) surgery using the remote ischemic preconditioning (RIPC) model, as well as to assess antioxidant balance with thioldisulfi de homeostasis (TDH). The secondary goal is to evaluate the impact of RIPC on TKA clinical outcomes. MATERIAL AND METHODS Patients in the ASA I-III group who underwent elective TKA were enrolled in this prospective, randomized, double-blind clinical research. TDH parameters were measured individually in groups with (Group I) and without (Group K) RIPC at the following times: preoperative (T0), right before the pneumatic tourniquet was opened (T1), 1 (T2), 6 (T3), and 24 (T4) hours after it was opened. In addition, at 3-hour intervals, the postoperative pain level was assessed using a visual analog scale (VAS). RESULTS This study included 60 cases (Group K; n=30, Group I; n=30). Both groups had equal native thiol, total thiol, disulfi de levels, disulfi de/native thiol, disulfi de/total thiol, and native thiol/total thiol ratios (p>0.05 for each). The change in native thiol, total thiol, and disulfi de values at T0 and T4 periods, however, was not statistically signifi cant for Group K (p=0.049, p=0.047, p=0.037, and p=0.217, p=0.191, p=0.220, respectively). At the 15th hour, VAS values in group I were considerably lower than in Group K (p=0.002). DISCUSSION This prospective, randomized, controlled trial examined how RIPC affected tourniquet-induced IRI-induced oxidative stress in TKA surgery. Lower native, total, and disulfi de levels at each postoperative time point were signifi cant. RIPC may reduce tourniquet-induced IRI-induced oxidative stress and TDH in TKA surgery. RIPC also reduced postoperative discomfort. CONCLUSIONS Our fi ndings suggest that RIPC may protect against the oxidative stress caused by IRI during limb surgery with a tourniquet and improve postoperative clinical outcomes. Key words: remote ischemic preconditioning, ischemia-reperfusion injury, thiol-disulfi de balance, oxidative stress, total knee arthroplasty.

Ischemic pre-conditioning has been shown to protect hearts against ischemia/reperfusion (I/R)-induced cardiac injury. However, it is not feasible in clinic. Many researchers have tried to introduce brief I/R in skeletal muscle to mimic cardiac ischemic pre-conditioning, called remote ischemia pre-conditioning (RIPC). Studies from our group and other groups have shown that RIPC induces the release of cytokines from skeletal muscle (myokines) for tissue protection. Myokines play a central role in repair, inflammatory, and immune responses after injury. Thus, the detailed protocol for RIPC might be useful for researchers to study mechanisms underlying RIPC-mediated tissue protection and crosstalk. Here, we describe a detailed RIPC protocol and show MG53 secretion after RIPC into the blood., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This review aims to highlight mechanistic insights on skeletal muscle ischemia/reperfusion injury (IRI), a potentially life-threatening complication after acute lower limb ischemia. Lower limb IRI produces a wide spectrum of manifestations, ranging from local skeletal muscle necrosis to multi-organ failure. There is increasing evidence from both in vitro and in vivo reports to demonstrate several promising interventions that have successfully reduced IRI in skeletal muscle ischemic models. However, clinical studies to confirm their benefits are still lacking., Methods: We conducted a comprehensive search of English literature listed in the PubMed database (All related published articles shown in PubMed until September 2020 have been included in this review), using the following keywords: acute limb ischemia, acute arterial occlusion, compartment syndrome, ischemic reperfusion injury, revascularization, and hypoxic reoxygenation., Results: A total of 58 articles pertinent to acute limb ischemia models were identified. The underlying mechanisms associated with IRI in skeletal muscle are due to excessive mitochondrial production of reactive oxygen species (ROS), cellular apoptosis and activation of inflammatory cascades. Several therapeutic interventions including both pharmacological and nonpharmacological treatments have been investigated and some showed promising results. These interventions include anti-oxidation, anti-inflammation, anti-hypertension, controlled-reperfusion, and ischemic preconditioning. Further clinical studies are needed to warrant their use in a clinical setting for lower limb IRI treatment., Conclusions: This review comprehensively summarizes the mechanisms underlying IRI in lower limb ischemia. The reports currently available regarding the potential therapeutic interventions against lower limb IRI from in vitro, in vivo and clinical studies are presented and discussed. These findings may provide mechanistic insights for devising the strategies to improve the clinical outcomes in IRI patients in the near future. Further clinical studies are needed to warrant their use in a clinical setting for lower limb IRI treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Remote ischaemic preconditioning (RIPC), induced by intermittent periods of limb ischaemia and reperfusion, confers cardiac and vascular protection from subsequent ischaemia-reperfusion (IR) injury. Early animal studies reliably demonstrate that RIPC attenuated infarct size and preserved cardiac tissue. However, translating these adaptations to clinical practice in humans has been challenging. Large clinical studies have found inconsistent results with respect to RIPC eliciting IR injury protection or improving clinical outcomes. Follow-up studies have implicated several factors that potentially affect the efficacy of RIPC in humans such as age, fitness, frequency, disease state and interactions with medications. Thus, realizing the clinical potential for RIPC may require a human experimental model where confounding factors are more effectively controlled and underlying mechanisms can be further elucidated. In this review, we highlight recent experimental findings in the peripheral circulation that have added valuable insight on the mechanisms and clinical benefit of RIPC in humans. Central to this discussion is the critical role of timing (i.e. immediate vs. delayed effects following a single bout of RIPC) and the frequency of RIPC. Limited evidence in humans has demonstrated that repeated bouts of RIPC over several days uniquely improves vascular function beyond that observed with a single bout alone. Since changes in resistance vessel and microvascular function often precede symptoms and diagnosis of cardiovascular disease, repeated bouts of RIPC may be promising as a preclinical intervention to prevent or delay cardiovascular disease progression., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Pulmonary ischemia and reperfusion (I/R) injury occurs in many clinical conditions and causes severe damage to the lungs. Diabetes mellitus (DM) predisposes to pulmonary I/R injury. We previously found that remote liver ischemia preconditioning protected lungs against pulmonary I/R injury. The aim of the present study was to investigate whether remote liver ischemic postconditioning (RLIPost) attenuates pulmonary damage induced by I/R injury in non-diabetic or diabetic rats. Male Sprague-Dawley rats were assigned into non-diabetic and diabetic groups. All rats except for the sham were exposed to 45 min of left hilum occlusion followed by 2 h of reperfusion. RLIPost was conducted at the onset of pulmonary reperfusion by four cycles of 5 min of liver ischemia and reperfusion. Lung injury was assessed by the wet/dry weight ratio, pulmonary oxygenation, histopathological changes, apoptosis and the expression of inflammatory cytokines. Reperfusion-associated protein phosphorylation states were determined. RLIPost offered strong pulmonary-protection in both non-diabetic and diabetic rats, as reflected in reduced water content and pulmonary structural damage, recovery of lung function, inhibition of apoptosis and inflammation after ischemia-reperfusion. RLIPost induced the activation of pulmonary STAT-3, a key component in the SAFE pathway, but not activation of the proteins in the RISK pathway, in non-diabetic rats. In contrast, RLIPost-induced pulmonary protection in diabetic lungs was independent of SAFE or RISK pathway activation. These results demonstrate that RLIPost exerts pulmonary protection against I/R-induced lung injury in non-diabetic and diabetic rats. The underlying mechanism for protection may be different in non-diabetic (STAT-3 dependent) versus diabetic (STAT-3 independent) rats., Competing Interests: The authors have declared that no competing interests exist.

Skin flaps are necessary in plastic and reconstructive surgery for the removal of skin cancer, wounds, and ulcers. A skin flap is a portion of skin with its own blood supply that is partially separated from its original position and moved from one place to another. The use of skin flaps is often accompanied by cell necrosis or apoptosis due to ischemia-reperfusion (I/R) injury. Proinflammatory cytokines, such as nuclear factor kappa B (NF-κB), inhibitor of kappa B (IκB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and oxygen free radicals are known causative agents of cell necrosis and apoptosis. To prevent I/R injury, many investigators have suggested the inhibition of proinflammatory cytokines, stem-cell therapies, and drug-based therapies. Ischemic preconditioning (IPC) is a strategy used to prevent I/R injury. IPC is an experimental technique that uses short-term repetition of occlusion and reperfusion to adapt the area to the loss of blood supply. IPC can prevent I/R injury by inhibiting proinflammatory cytokine activity. Various stem cell applications have been studied to facilitate flap survival and promote angiogenesis and vascularization in animal models. The possibility of constructing tissue engineered flaps has also been investigated. Although numerous animal studies have been published, clinical data with regard to IPC in flap reconstruction have never been reported. In this study, we present various experimental skin flap methods, IPC methods, and methods utilizing molecular factors associated with IPC.

Background: Ischemic preconditioning (IPC), either direct (DIPC) or remote (RIPC), is a procedure aimed at reducing the harmful effects of ischemia-reperfusion (I/R) injury., Objectives: To assess the local and systemic effects of DIPC, RIPC, and both combined, in the pig liver transplant model., Materials and Methods: Twenty-four pigs underwent orthotopic liver transplantation and were divided into 4 groups: control, direct donor preconditioning, indirect preconditioning at the recipient, and direct donor with indirect recipient preconditioning. The recorded parameters were: donor and recipient weight, graft-to-recipient weight ratio (GRWR), surgery time, warm and cold ischemia time, and intraoperative hemodynamic values. Blood samples were collected before native liver removal (BL) and at 0 h, 1 h, 3 h, 6 h, 12 h, 18 h, and 24 h post-reperfusion for the biochemical tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), creatinine, BUN (blood urea nitrogen), lactate, total and direct bilirubin. Histopathological examination of liver, gut, kidney, and lung fragments were performed, as well as molecular analyses for expression of the apoptosis-related BAX (pro-apoptotic) and Bcl-XL (anti-apoptotic) genes, eNOS (endothelial nitric oxide synthase) gene, and IL-6 gene related to inflammatory ischemia-reperfusion injury, using real-time polymerase chain reaction (RT-PCR)., Results: There were no differences between the groups regarding biochemical and histopathological parameters. We found a reduced ratio between the expression of the BAX gene and Bcl-XL in the livers of animals with IPC versus the control group., Conclusions: DIPC, RIPC or a combination of both, produce beneficial effects at the molecular level without biochemical or histological changes.

Objectives: We aimed to investigate the protective effect of remote ischemic preconditioning against spinal cord ischemia and find a clue to its mechanism by measuring glutamate concentrations in the spinal ventral horn., Methods: Male Sprague-Dawley rats were divided into 5 groups (n = 6 in each group) as follows: sham; SCI (only spinal cord ischemia); RIPC/SCI (perform remote ischemic preconditioning before spinal cord ischemia); MK-801/RIPC/SCI (administer MK-801, N-methyl-D-aspartate receptor antagonist, before remote ischemic preconditioning); and MK-801/SCI (administer MK-801 without remote ischemic preconditioning). Remote ischemic preconditioning was achieved by brief limb ischemia 80 minutes before spinal cord ischemia. MK-801 (1 mg/kg, intravenous) was administered 60 minutes before remote ischemic preconditioning. The glutamate concentration in the ventral horn was measured by microdialysis for 130 minutes after spinal cord ischemia. Immunofluorescence was also performed to evaluate the expression of N-methyl-D-aspartate receptor 2B subunit in the ventral horn 130 minutes after spinal cord ischemia., Results: The glutamate concentrations in the spinal cord ischemia group were significantly higher than in the sham group at all time points (P < .01). Remote ischemic preconditioning attenuated the spinal cord ischemia-induced glutamate increase. When MK-801 was preadministered before remote ischemic preconditioning, glutamate concentration was increased after spinal cord ischemia (P < .01). Immunofluorescence showed that remote ischemic preconditioning prevented the increase in the expression of N-methyl-D-aspartate receptor 2B subunit on the surface of motor neurons (P = .047)., Conclusions: Our results showed that remote ischemic preconditioning prevented spinal cord ischemia-induced extracellular glutamate increase in ventral horn and suppressed N-methyl-D-aspartate receptor 2B subunit expression., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Pharmacological conditioning is a protective strategy against ischemia/reperfusion injury, which occurs during liver resection and transplantation. Polyethylene glycols have shown multiple benefits in cell and organ preservation, including antioxidant capacity, edema prevention and membrane stabilization. Recently, polyethylene glycol 35 kDa (PEG35) preconditioning resulted in decreased hepatic injury and protected the mitochondria in a rat model of cold ischemia. Thus, the study aimed to decipher the mechanisms underlying PEG35 preconditioning-induced protection against ischemia/reperfusion injury. A hypoxia/reoxygenation model using HepG2 cells was established to evaluate the effects of PEG35 preconditioning. Several parameters were assessed, including cell viability, mitochondrial membrane potential, ROS production, ATP levels, protein content and gene expression to investigate autophagy, mitochondrial biogenesis and dynamics. PEG35 preconditioning preserved the mitochondrial function by decreasing the excessive production of ROS and subsequent ATP depletion, as well as by recovering the membrane potential. Furthermore, PEG35 increased levels of autophagy-related proteins and the expression of genes involved in mitochondrial biogenesis and fusion. In conclusion, PEG35 preconditioning effectively ameliorates hepatic hypoxia/reoxygenation injury through the enhancement of autophagy and mitochondrial quality control. Therefore, PEG35 could be useful as a potential pharmacological tool for attenuating hepatic ischemia/reperfusion injury in clinical practice.

Transient ischaemia and reperfusion in liver tissue induce hepatic ischaemia/reperfusion (I/R) tissue injury and a profound inflammatory response in vivo. Hepatic I/R can be classified into warm I/R and cold I/R and is characterized by three main types of cell death, apoptosis, necrosis and autophagy, in rodents or patients following I/R. Warm I/R is observed in patients or animal models undergoing liver resection, haemorrhagic shock, trauma, cardiac arrest or hepatic sinusoidal obstruction syndrome when vascular occlusion inhibits normal blood perfusion in liver tissue. Cold I/R is a condition that affects only patients who have undergone liver transplantation (LT) and is caused by donated liver graft preservation in a hypothermic environment prior to entering a warm reperfusion phase. Under stress conditions, autophagy plays a critical role in promoting cell survival and maintaining liver homeostasis by generating new adenosine triphosphate (ATP) and organelle components after the degradation of macromolecules and organelles in liver tissue. This role of autophagy may contribute to the protection of hepatic I/R-induced liver injury; however, a considerable amount of evidence has shown that autophagy inhibition also protects against hepatic I/R injury by inhibiting autophagic cell death under specific circumstances. In this review, we comprehensively discuss current strategies and underlying mechanisms of autophagy regulation that alleviates I/R injury after liver resection and LT. Directed autophagy regulation can maintain liver homeostasis and improve liver function in individuals undergoing warm or cold I/R. In this way, autophagy regulation can contribute to improving the prognosis of patients undergoing liver resection or LT., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The protective effect of remote ischemic preconditioning (RIPC) against liver ischemia-reperfusion injury caused by hepatectomy remains controversial. We conducted this meta-analysis to evaluate the effectiveness and safety of RIPC strategies. PubMed, SinoMed, Embase, Cochrane Library, Medline, and Web of Science databases were searched for randomized controlled trials (RCT) that assessed the effectiveness and safety of RIPC strategies. The primary outcomes were operation time, index of liver function on postoperative day (POD) 1, postoperative complications, and postoperative hospital stay. The pooled odds ratios and weighted mean differences at 95% confidence interval (95% CI) were estimated using a fixed-effects or random-effects model. A total of 459 patients were included in seven RCTs. The alanine aminotransferase (ALT) and alanine aminotransferase (AST) values on POD1 were significantly different between the RIPC group and the N-RIPC group (P = 0.009 and P = 0.02, respectively). However, the heterogeneity was significant (I 2  = 84% and I 2  = 86%), and the results of a sensitivity analysis were unstable. There was no significant difference in the total bilirubin levels (P = 0.25) between the two groups on POD1. Subgroup analysis revealed no significant difference in the AST and ALT levels on POD1 between the RIIPC group and the N-RIPC group, regardless of whether the vascular control technique was used (all P > 0.05). Based on current evidence, RIPC does not alleviate liver injury caused by IRI after hepatectomy., (© 2021. Springer Nature Singapore Pte Ltd.)

Ischemia reperfusion injury (IRI) is associated with a broad array of life-threatening medical conditions including myocardial infarct, cerebral stroke, and organ transplant. Although the pathobiology and clinical manifestations of IRI are well reviewed by previous publications, IRI-related transcriptomic alterations are less studied. This study aimed to reveal a transcriptomic hallmark for IRI by using the RNA-sequencing data provided by several studies on non-human preclinical experimental models. In this regard, we focused on the transcriptional responses of IRI in an acute time-point up to 48 h. We compiled a list of highly reported genes in the current literature that are affected in the context of IRI. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and found many of the up-regulated genes to be involved in cell survival, cell surface signaling, response to oxidative stress, and inflammatory response, while down-regulated genes were predominantly involved in ion transport. Furthermore, by GO analysis, we found that multiple inflammatory and stress response processes were affected after IRI. Tumor necrosis factor alpha (TNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways were also highlighted in the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In the last section, we discuss the treatment approaches and their efficacy for IRI by comparing RNA sequencing data from therapeutic interventions with the results of our cross-comparison of differentially expressed genes and pathways across IRI.

Background: To investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function., Methods: Four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning., Results: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05)., Conclusion: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels., (© 2021. The Author(s).)

We assessed the effects and potential mechanism of romote ischemic preconditioning (RIPC) on leukocytes-endothelium cell adhesion in the flap microvessel after ischemia-reperfusion (I/R) injury. Eight hours after reperfusion, edema and intravascular leukocyte aggregation were reduced and microvessels were more obvious in the group with superficial inferior epigastric artery (SIEA) perforator flap (SIEA-flap) subjected to RIPC than in the I/R group. Zinc finger protein 667 (ZNF667) was significantly increased but P-selectin was decreased in the flaps subjected to RIPC, compared to those in the I/R group. The low expression of P-selectin was associated with ZNF667 expression and activation in human dermal microvascular endothelial cells in response to hypoxic preconditioning. ZNF667 bound to the P-selectin promoter region, suppressing its transcription through a special core sequence. The ablation of P-selectin by small interfering RNA effectively prevented the leukocytes-endothelium cell adhesion effect of ZNF667-knockdown. ZNF667 upregulation attenuates leukocyte-endothelial cell adhesion by negatively regulating the expression of P-selectin in SIEA-flap subjected to RIPC., (© 2021 International Federation for Cell Biology.)

Ischemic preconditioning (IPC) significantly reduces ischemia-reperfusion injury in the brain by inducing ischemic tolerance. Although emerging evidence suggests that microRNAs (miRNAs) contribute to the pathogenesis of brain ischemia and IPC-induced neuroprotection, the role of miRNAs and their underlying mechanisms are still unclear. IPC was induced in male C57BL/6 mice by brief bilateral common carotid artery occlusion. After 24 h, mice underwent transient middle cerebral artery occlusion followed by 3 h of reperfusion. Expression levels of messenger RNAs (mRNAs) and proteins were examined in the ipsilateral cortex, and mimics and inhibitors of selective miRNAs were transfected into Neuro-2a cells before oxygen-glucose deprivation (OGD). Post-IPC miRNA expression profiling identified neuroprotection-associated changes in miRNA expression in the ipsilateral cortex after ischemic stroke. Among them, miR-33-5p and miR-135b-5p were significantly downregulated by IPC. Inhibition of miR-33-5p and miR-135b-5p expression protected Neuro-2a cells from OGD-induced apoptosis. Inhibition of these two miRNAs significantly increased mRNA and protein levels of ATP-binding cassette subfamily A member 1 (ABCA1), and a binding assay showed that these two miRNAs showed specificity for Abca1 mRNA. Overexpression of ABCA1 decreased the Bax/Bcl2 mRNA ratio and activation of caspase-9 and caspase-3, whereas knockdown of ABCA1 expression increased the Bax/Bcl2 mRNA ratio and the percentage of Neuro-2a cells with a loss of mitochondrial membrane potential after OGD-treatment. In conclusion, ABCA1 expression is regulated by miR-33-5p and miR-135b-5p. Increased ABCA1 expression following IPC exerts a protective influence against cerebral ischemia via suppression of a mitochondria-dependent apoptosis pathway.

New Findings: What is the central question of this study? Animal infarct studies indicate a delayed window of cardiac protection after remote ischaemic preconditioning (RIPC); however, the presence and duration of this delayed effect have not been examined in human microvasculature in vivo. What is the main finding and its importance? Cutaneous vasodilatation induced by local heating or ACh was increased significantly 24 and 48 h after a single bout of RIPC, respectively. Neither response persisted beyond ∼48 h. Sodium nitroprusside-induced cutaneous vasodilatation was not altered. These findings reveal a delayed increase in microvascular endothelial function after a single bout of RIPC., Abstract: Remote ischaemic preconditioning (RIPC) induces protective effects from ischaemia-reperfusion injury. In the myocardium and conduit vasculature, a single bout of RIPC confers delayed protection that begins 24 h afterwards and lasts for 2-3 days. However, the extent and the time line in which a single bout of RIPC affects the human microvasculature are unclear. We hypothesized that a single bout of RIPC results in a delayed increase in skin microvascular function. Sixteen healthy participants (age, 23 ± 4 years; seven males, nine females; MAP, 82 ± 7 mmHg) were recruited to measure cutaneous microvascular function immediately before a single bout of RIPC and 24, 48 and 72 h and 1 week after the bout. The RIPC consisted of four repetitions of 5 min of arm blood flow occlusion interspersed by 5 min reperfusion. Skin blood flow responses to local heating (local temperature of 42°C), ACh and sodium nitroprusside were measured by laser speckle contrast imaging and expressed as the cutaneous vascular conductance (CVC; in perfusion units per millimetre of mercury). Vasodilatation in response to local heating was increased 24 and 48 h after RIPC (ΔCVC, 1.05 ± 0.07 vs. 1.18 ± 0.07 and 1.24 ± 0.08 PU mmHg -1 , pre- vs. 24 and 48 h post-RIPC; P < 0.05). Acetylcholine-induced cutaneous vasodilatation increased significantly 48 h after RIPC (ΔCVC, 0.71 ± 0.07 vs. 0.93 ± 0.12 PU mmHg -1 , pre- vs. 48 h post-RIPC; P < 0.05) and returned to baseline thereafter. Sodium nitroprusside-mediated vasodilatation did not change. Thus, a single bout of RIPC elicited a delayed response in the microvasculature, resulting in an improvement in the endothelium-dependent cutaneous vasodilatory response that peaked ∼48 h post-RIPC., (© 2021 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Cerebral ischemia/reperfusion injury causes a series of intricate cascade reactions in brain tissue causing apoptosis and proinflammatory programmed cell death known as pyroptosis of nerve cells. The dysfunction of target organelle mitochondria plays a key role in the process of neuronal apoptosis and pyroptosis. Mesenchymal stem cells (MSCs) have been widely used in the experimental or clinical treatment of various ischemic diseases, but the therapeutic efficacy of MSCs on cerebral ischemia-reperfusion injury need to be improved. We successfully cultured olfactory mucosa MSCs (OM-MSCs) to obtain a better source of seed cells. In this way, the therapeutic potential of OM-MSCs transplantation has been evaluated for ischemic stroke using an optimized culture scheme in vitro . Ischemic-hypoxic preconditioned OM-MSCs (IhOM-MSCs) were used to treat a neuron model of oxygen-glucose deprivation/reperfusion and the middle cerebral artery occlusion in rats. These results demonstrated that IhOM-MSCs mediated the upregulation of the downstream target genes GRP78 and Bcl-2 by miR-181a to protect mitochondrial function and inhibit apoptosis and pyroptosis of neurons in the ischemia/reperfusion injury model. Thus, IhOM-MSCs transplantation may be an effective therapy of ischemic stroke in the future.

Primary graft dysfunction (PGD) and ischemia-reperfusion injury (IRI) occur in up to 30% of patients undergoing lung transplantation and may impact on the clinical outcome. Several strategies for the prevention and treatment of PGD have been proposed, but with limited use in clinical practice. In this study, we investigate the potential application of sevoflurane (SEV) preconditioning to mitigate IRI after lung transplantation. The study included two groups of swines (preconditioned and not preconditioned with SEV) undergoing left lung transplantation after 24-hour of cold ischemia. Recipients' data was collected for 6 hours after reperfusion. Outcome analysis included assessment of ventilatory, hemodynamic, and hemogasanalytic parameters, evaluation of cellularity and cytokines in BAL samples, and histological analysis of tissue samples. Hemogasanalytic, hemodynamic, and respiratory parameters were significantly favorable, and the histological score showed less inflammatory and fibrotic injury in animals receiving SEV treatment. BAL cellular and cytokine profiling showed an anti-inflammatory pattern in animals receiving SEV compared to controls. In a swine model of lung transplantation after prolonged cold ischemia, SEV showed to mitigate the adverse effects of ischemia/reperfusion and to improve animal survival. Given the low cost and easy applicability, the administration of SEV in lung donors may be more extensively explored in clinical practice., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Alessandro Bertani et al.)

Fluid resuscitation after hemorrhagic shock is a model of systemic ischemia/reperfusion injury (SI/RI), and the liver is one of the main target organs. Ischemic preconditioning (IPC) can reduce hepatic ischemia-reperfusion injury (I/RI) via autophagy. However, whether remote ischemic preconditioning (RIPC) can alleviate the liver injury that is secondary to hemorrhagic shock and the role of autophagy in this process remain unclear. Thus, we constructed a hemorrhagic shock model in rats with or without RIPC to monitor mean arterial pressure (MAP) and investigate liver secondary injury levels via serum aminotransferase, ultrasound, HE staining and TUNEL fluorescence staining. We also detected levels of serum inflammatory factors including tumor necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β) by enzyme-linked immunosorbent assay (ELLSA), observed autophagosomes by Transmission electron microscopy (TEM), and analyzed LC3, Beclin-1, p62 protein expression levels by immunohistochemical (IHC) and western blot (WB). We found that RIPC increased blood pressure adaptability, decreased lactate (Lac) and aminotransferase levels, and delayed the decrease in liver density. Levels of inflammatory factors TNF-α, IL-1β and apoptosis were attenuated, autophagosomes was increased in the RIPC group compared with controls. IHC and WB both revealed increased LC3 and Beclin-1 but decreased p62 protein expression levels in the RIPC group. Together, our data suggest that RIPC-activated autophagy could play a protective role against secondary liver injury following hemorrhagic shock., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Propofol is widely used in general anesthesia, and it has been reported to protect various organs against ischemia-reperfusion injury (IRI), including liver. To evaluate the hepatoprotective effects of ischemic preconditioning (IP) under propofol anesthesia, we investigated the possible underlying mechanisms in rats., Methods: Male Sprague-Dawley rats were randomly assigned to 3 groups: sham group (n = 5), non-IP group (n = 9; 45 minutes of hepatic ischemia followed by 2 hours of reperfusion), and IP group (n = 9; IP applied as 10 minutes of hepatic ischemia followed by 15 minutes of reperfusion before 45 minutes of ischemia). Anesthesia was maintained with intravenous (IV) infusion of propofol (800 μg/kg/min). Liver enzymes, histopathological changes, and cytokine expression were examined., Results: The IP group showed significantly lower liver enzyme levels (aspartate aminotransferase, P = .045; alanine aminotransferase, P = .006) and reduced the histologic grades of hepatic injury 2 hours after reperfusion (P = .004) compared to the non-IP group. Lactate dehydrogenase activity (P < .001) and interleukin-6 mRNA levels were significantly higher in the non-IP group than in the sham and IP groups (P = .002, both groups)., Conclusions: Our results demonstrate that IP under propofol anesthesia significantly attenuated hepatic IRI. The principal mechanism of the protective effects appeared to involve reduced expression of the IL-6 pro-inflammatory cytokine and subsequent reduction of the degree of necrosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Ischaemia/reperfusion (I/R) injury is defined as the damage to the tissue which is caused when blood supply returns to tissue after ischaemia. To protect the ischaemic tissue from irreversible injury, various protective agents have been studied but the benefits have not been clinically applicable due to monotargeting, low potency, late delivery or poor tolerability., Key Findings: Strategies involving preconditioning or postconditioning can address the issues related to the failure of protective therapies. In principle, postconditioning (PoCo) is clinically more applicable in the conditions in which there is unannounced ischaemic event. Moreover, PoCo is an attractive beneficial strategy as it can be induced rapidly at the onset of reperfusion via series of brief I/R cycles following a major ischaemic event or it can be induced in a delayed manner. Various pharmacological postconditioning (pPoCo) mechanisms have been investigated systematically. Using different animal models, most of the studies on pPoCo have been carried out preclinically., Summary: However, there is a need for the optimization of the clinical protocols to quicken pPoCo clinical translation for future studies. This review summarizes the involvement of various receptors and signalling pathways in the protective mechanisms of pPoCo., (© 2020 Royal Pharmaceutical Society.)

Background: Hepatic ischemia reperfusion injury often leads to increased complications and mortality after surgery. Although ischemic preconditioning is used as a convenient and effective method to protect the liver from warm ischemia reperfusion injury, the optimal protocol is currently unclear. Therefore, in this study, we sought to identify ideal conditions and methods for ischemic preconditioning. Materials and methods : We compared several preconditioning protocols of the ischemia/reperfusion (I/R) cycle in 30 male Sprague-Dawley rats (5 groups, n = 6), including relevant sham and I/R injury (no preconditioning) controls. Experimental group conditions included: (1) ischemia for 5 min/reperfusion for 10 min (ischemic preconditioning 1, IPC-1); (2) ischemia for 5 min/reperfusion for 5 min, repeated three times (IPC-2); and (3) ischemia for 10 min/reperfusion for 10 min (IPC-3). Readouts included transaminase activity levels measured from collected sera, and histopathological changes, liver cell apoptosis, superoxide dismutase (SOD) activity, glutathione (GSH) levels, and malondialdehyde (MDA) levels measured from collected liver tissue segments subjected to warm ischemia (that is from the 70% of the liver mass that had been deprived from blood flow during the ischemia phase). Results: Compared to the I/R control group, the IPC-1, IPC-2, and IPC-3 groups all showed significant decreases in liver transaminase activity levels, alleviation of pathological injury-associated changes, and a decrease in liver cell apoptosis. Moreover, SOD activity and GSH content were increased while MDA content was decreased in the three experimental groups. Compared to the IPC-1 and IPC-3 groups, the changes in the IPC-2 group were the most significant ( P  < 0.05). Conclusions: Ischemic preconditioning can reduce hepatic warm ischemia reperfusion injury in rats. The IPC-2 protocol, involving ischemia for 5 min and reperfusion for 5 min, repeated three times, provided the optimal protection against hepatic ischemia reperfusion injury among the protocols studied.

Cardiac arrest is one of the major causes of death and disability. The aim of the study was to identify dynamic time-dependent metabolomic changes reflected in rat plasma induced by cerebral ischemia and reperfusion with the focus on the protective effect of ischemic preconditionig. Global cerebral ischemia in rats was induced by the four-vessel occlusion. Blood plasma was collected in three reperfusion times: an early post-acute 3 hr, then 24 hr, as an incipient time for delayed neuronal death induction and 72 hr as prolonged reperfusion period. The metabolomic measurements were conducted via untargeted nuclear magnetic resonance spectroscopy. Plasma of ischemized rats manifested dynamic metabolomic changes over the reperfusion time, such as increased levels of ketone bodies, decreased levels of pyruvate, alanine, and citrate. All three branched chain amino acids showed common pattern during reperfusion time: a decrease in 3 hr compared to sham, then a highest level in 24 hr and decrease in 72 hr reperfusion time, similar to their corresponding ketoacids. The protective effect of ischemic preconditioning was demonstrated by a faster tendency of plasma metabolites to normalize. Results also proved the remarkable metabolomic differences between the control (naïve) and sham-operated anesthetized animals, what warrants for critical evaluation of surgery/anaesthesy in the algorithm of metabolomic animal studies., (© 2020 International Union of Biochemistry and Molecular Biology.)

Background: Peripheral arterial disease has high incidence and complication rates. Vessel recanalization represents the main therapy. However, it induces reperfusion injury. Preconditioning with sildenafil has been advocated to protect against this injury. In this study, we show a real-time noninvasive quantitative assessment using hyperspectral imaging (HSI) of ischemia/reperfusion (IR) and analyzing the sildenafil effect. Materials and Methods: A one-sided hindlimb ischemia (120 minutes) followed by reperfusion (30 minutes) was created. Five mice received Sildenafil (1 mg/kg, i.p. twice before ischemia) and 5 mice served as control. The StO 2 at T0, 5, 30, 60, 120 minutes after ischemia (T5, 30, 60, 120) and 5, 15, and 30 minutes after reperfusion (T125, 135, 150) were measured through HSI. Results: The control group showed a significantly lower StO 2 at T120 (24.8% ± 17%) as compared with T0 (53.3% ± 7.04%) ( P  = .013) and T150 (76.8 ± 3.77; P  = .0008). T150 showed a statistically significantly higher StO 2 than T0 ( P  = .0134). In the sildenafil group, T120 StO 2 (28.6% ± 20%) was lower than T0 (63.3% ± 8.46%; P  = .0312) and T150 (73.3% ± 19.1%, P  = .0075). The StO 2 values did not differ statistically between sildenafil and control groups. Conclusions: HSI is a feasible tool to quantify both ischemia and reperfusion phases during lower limb IR. Preconditioning with sildenafil did not modify IR-related StO 2 changes.

Background: Open surgical repair (OSR) for thoracoabdominal aortic aneurysms (TAA) is associated with a high pulmonary and renal morbidity rate. Ischemic preconditioning (IPC) is a mechanism of protection against the deleterious effects of ischemia-reperfusion. To our knowledge IPC has never been tested during OSR for TAA., Methods: The primary objective of the study is to evaluate the efficacy of IPC during OSR for TAA with respect to acute kidney injury (AKI) according to KDIGO and pneumonia/prolonged ventilation-time during the first 8 postoperative days. The secondary objectives are to compare both arms with respect to cardiac complications within 48 h, renal and pulmonary complications within 21 days and mortality at 60 days. To assess the efficacy of IPC with respect to pulmonary and renal morbidity, a cox model for competing risks will be used. Assuming that the event occurs among 36% of the patients when no IPC is performed, the allocation of 55 patients to each arm should allow detecting a hazard ratio of at least 2.75 with a power of 80% when admitting 5% for an error of first kind. This means that 110 patients, enrolled in this multicenter study, may be randomised within 36 months of the first randomization. Randomization will be performed to allocate patients either to surgery with preconditioning before aortic cross clamping (Arm 1) or to surgery without preconditioning before aortic cross clamping (Arm 2). Randomization takes place during the intervention after intravenous injection of heparin, or after the start of femoral assistance. The procedure for IPC will be a supra-visceral thoracic aortic cross clamping for 5 min followed by an unclamping period of 5 min. This procedure will be repeated twice before starting thoracic aortic cross clamping needed to perform surgery., Conclusions: Our hypothesis is that ischemic preconditioning could reduce clinical morbidity and the incidence of lung damage associated with supra-visceral aortic clamping., Trial Registration: EPICATAStudy registered in ClinicalTrial.gov / number: NCT03718312 on Oct.24.2018 URL number.